NOVEL PARS INHIBITOR FOR ACETAMINOPHEN INTOXICATION

新型 PARS 抑制剂可治疗对乙酰氨基酚中毒

• 批准号: 2872265
• 负责人: JON G MABLEY
• 金额: $ 11.65万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2872265
• 关键词: ADP ribosylation; AP1 protein; DNA damage; acetaminophen; acute disease /disorder; antiinflammatory agents; chemoprevention; cytotoxicity; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; enzyme activity; enzyme inhibitors; laboratory rat; liver pharmacology; liver toxic disorder; macrophage; nitric oxide; nitric oxide synthase; nonhuman therapy evaluation; pentosyltransferase; peroxidation; peroxynitrites; pyrones; transaminases

The acute hepatotoxicity of acetaminophen is a major health concern since this analgesic is one of the most commonly used drugs in intentional overdose. Current treatment regimens for acetaminophen-induced hepatotoxicity have limited efficacy. A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has now been strongly implicated in the pathogenesis of acetaminophen-induced hepatotoxicity. PARS activation induces AP-1 dependent pro-inflammatory gene expression and NAD consumption, resulting in ATP depletion, cellular energetic failure, granulocytic infiltration, and end-organ injury. In this proposal, we present experimental evidence that pharmacologic inhibition of PARS activity and genetic ablation of the PARS gene have potent anti-inflammatory effects and dramatically protect against acetaminophen-induced injury. Inotek is developing a highly potent, specific, non-toxic, and proprietary PARS inhibitor, 5-iodo-6-amino-1,2-benzopyrone (INH2BP). INH2BP requires demonstration of efficacy in a clinically relevant and stringent experimental model of acetaminophen intoxication in order to justify its commercialization as a novel anti-inflammatory agent for the prevention of liver failure. In this proposal, we will test the protective effect of INH2BP, administered at various timepoints and dose levels, in comparison with N- acetyl cysteine, the current gold standard of clinical therapy. Biological endpoints, indicative of therapeutic efficacy, will include neutrophil infiltration, histiologic damage, poly ADP-ribose formation, lipid peroxidation, and serum transaminasemia. The demonstration that INH2BP is effective in this model in a post-exposure paradigm would represent a breakthrough in the design of novel regimens for the treatment of acetaminophen intoxication and would justify its further commercial development. PROPOSED COMMERCIAL APPLICATIONS: The domestic market for a novel, effective therapy for acetaminophen intoxication is estimated at $250 million per annum. Global markets are estimated at $800 million. Current market entrants have limited efficacy: massive acetaminophen intoxication frequently results in fulminant liver failure necessitating orthotopic liver transplantation. INH2BP may represent the first highly potent and successful adjunct to the current therapeutic regimen; funding of SBIR Phases I and II will allow for market entry in 4 years.

对乙酰氨基酚的急性肝毒性是一个主要的健康问题，因为这种镇痛药是故意过量使用的最常用药物之一。目前对乙酰氨基酚引起的肝毒性的治疗方案疗效有限。最近发现的一种炎症损伤机制“聚（adp -核糖）合成酶（PARS）途径”，目前已被认为与对乙酰氨基酚诱导的肝毒性的发病机制密切相关。PARS激活诱导AP-1依赖性促炎基因表达和NAD消耗，导致ATP耗竭、细胞能量衰竭、粒细胞浸润和终末器官损伤。在这一提议中，我们提供了实验证据，证明药物抑制PARS活性和基因消融PARS基因具有有效的抗炎作用，并显著保护对乙酰氨基酚引起的损伤。Inotek正在开发一种高效、特异性、无毒、专有的PARS抑制剂，5-碘-6-氨基-1,2-苯并吡酮（INH2BP）。INH2BP需要在临床相关且严格的对乙酰氨基酚中毒实验模型中证明其有效性，以证明其作为预防肝衰竭的新型抗炎药的商业化。在本提案中，我们将测试在不同时间点和剂量水平给药的INH2BP的保护作用，并与目前临床治疗的金标准N-乙酰半胱氨酸进行比较。指示治疗效果的生物学终点包括中性粒细胞浸润、组织损伤、聚adp核糖形成、脂质过氧化和血清转氨血症。INH2BP在暴露后模型中有效的证明，将代表着对乙酰氨基酚中毒治疗新方案设计的突破，并将证明其进一步的商业开发是合理的。拟议的商业应用：对乙酰氨基酚中毒的新型有效疗法的国内市场估计为每年2.5亿美元。全球市场估计为8亿美元。目前市场进入者的疗效有限：大量对乙酰氨基酚中毒经常导致暴发性肝衰竭，需要原位肝移植。INH2BP可能是目前治疗方案的第一种高效且成功的辅助药物；SBIR第一期和第二期的资金将允许在4年内进入市场。